Process for the synthesis C-2, C-3 substituted N-alkylated indoles useful as CPLA2 inhibitors

ABSTRACT

The present invention provides method for making a compound of formula 1:  
                 
 
comprising the steps of reacting compounds of formulas 2 and 3:  
                 
 
to produce a compound of formula 4:  
                 
 
wherein R 1 , R 2 , R 3 , R 4  and R 5  are defined as described herein. The compound of formula 4 is then converted to the compound of formula 1. The invention further comprises compounds of formulas 3 and 4 and methods for making compounds of formulas 3 and 4.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. Provisional ApplicationSer. No. 60/603,124 filed Aug. 19, 2004, which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

This invention relates to a process for making substituted indolesuseful as cPLA₂ inhibitors and intermediate compounds in that process.

BACKGROUND

Processes for alkylating the C-3 position of indoles are well known inthe art. The effect of different metal cations, base concentration, andcatalysts for the phase transfer alkylation of indoles under basicconditions has been studied. Alkylation of indoles can also proceed withcatalytic amounts of acid. Trifluoroacetic acid and triethylsilane havebeen used in combination to simultaneously alkylate and reduce at theC-3 position of indoles. However, trifluoroacetic acid is incompatiblewith some acid sensitive functional groups, such as benzhydryl groups.

Known methods for producing N-alkylated indoles generally requireexpensive materials and processing. An efficient and economical methodfor producing N-alkylated indoles is therefore desirable.

SUMMARY OF THE INVENTION

The present invention provides method for making a compound of formula1:

comprising the steps of reacting compounds of formulas 2 and 3:

to produce an intermediate compound of formula 4:

wherein R¹, R², R³, R⁴ and R⁵ are defined as described herein. Thereaction occurs in the presence of a base, a palladium catalyst, and acopper catalyst. The compound of formula 4 is then converted to thecompound of formula 1.

The invention further comprises compounds of formulas 3 and 4 andmethods for making compounds of formulas 3 and 4.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The coupling reaction of a compound of formula 3, above, withN-substituted 2-iodo, 4-chloro anilines requires different reactionconditions depending on the identity of the aniline amino substituent.When the amino substituent is a trifluoroacetyl group, for example, thereaction is facile with relatively low levels of catalysts (e.g., about1 mole % Pd catalyst and 2 mole % CuI) at moderate temperatures (e.g.,less than 50° C.). However, when the amino substituent is a benzhydrylgroup, more Pd catalyst (e.g., about 5 mole % or more) is necessary,which increases the cost and complexity of the synthesis andpurification.

It has been discovered that the coupling reaction of compounds offormulas 2 and 3 will proceed efficiently to produce the compound offormula 4 in high yield when the amount of palladium catalyst is reduced(e.g., about 0.5 mole % to about 1.5 mole %), provided that the coppercatalyst is present in at least about 5 mole % and at least about 2equivalents (i.e., about 200 mole %) of a base is used. The use of lesspalladium catalyst makes the method of the invention more efficient andeconomical.

The present invention provides method for making a compound of formula1:

comprising the steps of reacting compounds of formulas 2 and 3:

to produce an intermediate compound of formula 4:

wherein R¹, R², R³, and R⁴ each is independently selected from the groupconsisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl, and R⁵ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl. The reaction occurs in the presence of a base, apalladium catalyst, and a copper catalyst. The compound of formula 4 isthen converted to the compound of formula 1.

In some embodiments, R¹, R², R³, and R⁴ each is independently selectedfrom the group consisting of H, halogen, —CF₃, and —C₁₋₆ alkyl. Incertain embodiments, R¹ is H, R² is Cl, R³ is Cl, and R⁴ is H. In otherembodiments, R¹ is —CF₃, R² is H, R³is H, and R⁴ is H.

At least about 2 equivalents (e.g., about 2-4 equivalents, or about 3equivalents) of base may be present in the reaction mixture. Suitablebases include, for example, trialkylamines (e.g., diisopropylethylamineor triethylamine), alkali earth metal carbonates (e.g., lithiumcarbonate, sodium carbonate, potassium carbonate, or cesium carbonate),alkali earth metal bicarbonates (e.g., lithium bicarbonate, sodiumbicarbonate, potassium bicarbonate, or cesium bicarbonate), alkalineearth metal carbonates (e.g., magnesium carbonate, calcium carbonate, orbarium carbonate), and alkaline earth metal bicarbonates (e.g.,magnesium bicarbonate, calcium bicarbonate, or barium bicarbonate).

The palladium catalyst may be present in about 0.5 mole % to about 1.5mole %. Any palladium catalyst useful in Sonogashira-type couplingreactions may be used, including, for example, PdCl₂(PPh₃)₂, Pd(PPh₃)₄,Pd(CN)₂Cl₂, Pd(OAc)₂, and PdCl₂ with appropriate phosphine ligands suchas PPh₃, P(cyclohexyl)₃, or P(t-butyl)₂methyl.

The copper catalyst may be present in at least about 5:mole % (e.g., 5mole % to about 15 mole %, or about 10 mole %). Any copper catalystuseful in Sonogashira-type coupling reactions may be used, including,for example, copper iodide (CuI).

Organic bases (e.g., trialkylamines) may be removed by distillation ofthe product mixture, typically under reduced pressure. An alcohol, suchas isopropanol, may be added to keep minor impurities dissolved whilethe compound of formula 4 is precipitated by addition of ananti-solvent, such as water, which obviates the need to separate theproduct from water-soluble inorganic bases (e.g., alkalai and alkalineearth metal carbonates and bicarbonates). Using the process of thisinvention, compounds of formula 4 may be obtained in yields of at leastabout 90%, and at purities of at least about 95%.

The compound of formula 4 may be reacted with copper iodide to produce acompound of formula 5:

The compound of formula 5 may be reacted with a compound of formula 6:

to produce a compound of formula 7:

The compound of formula 7 may be reacted with a base to remove the esterC₁₋₆ alkyl group and produce the compound of formula 1. The compound offormula 7 may be isolated by crystallization prior to reacting with thebase, or alternatively, the compound of formula 7 may be reacted withthe base without prior purification.

The compound of formula 1 may be purified, for example, byrecrystallization from an alcohol, such as ethanol.

The compound of formula 2 can be prepared by reacting2-iodo-4-chloroaniline (obtained, for example, by iodination ofp-chloroaniline, or by any other method known in the art) withbenzhydrol in the presence of an acid such as an organic sulfonic acid(e.g., benzenesulfonic acid, p-toluenesulfonic acid, or the like), in anaprotic solvent (e.g., acetonitrile, toluene, or the like). In someembodiments this reaction proceeds slowly and requires slow addition ofthe benzhydrol to the 2-iodo-4-chloroaniline to achieve a good yield.Addition and reaction times can be reduced without reducing the yield orpurity of the product by heating the reaction, for example, to at leastabout 75° C., or at least about 80° C., or to the reflux temperature ofthe solvent. The compound of formula 2 thus produced may be purified byprecipitation and filtration, followed by trituration with a solvent(e.g., methanol) to remove impurities. The compound can be obtained in apurity of at least about 90% (e.g., about 98-99%) by this method.

The compound of formula 3 may be prepared by reacting a compound offormula 8 with a compound of formula 9:

in the presence of a base, wherein R⁵ is —C(O)O—C₁₋₆ alkyl (such as, forexample, tert-butoxycarbonyl).

The invention also provides a method for making a compound of formula 4:

according to the methods described above. The invention further providescompounds of formula 4.

The invention further provides compounds of formula 3:

wherein R¹, R², R³, and R⁴ each is independently selected from the groupconsisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl, and R⁵ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl. In some embodiments, R¹, R², R³, and R⁴ each isindependently selected from the group consisting of H, halogen, —CF₃,and —C₁₋₆ alkyl. In certain embodiments, R¹ is H, R² is Cl, R³ is Cl,and R⁴ is H. In other embodiments, R¹ is —CF₃, R² is H, R³ is H, and R⁴is H. In still other embodiments, R¹ is CH₃, R² is H, R³ is H, and R⁴ isCH₃. Examples of compounds of formula 3 includeN-but-3-ynyl-C-(2,6-dimethylphenyl)methanesulfonamide,N-but-3-ynyl-C-(3,4-dichlorophenyl)methanesulfonamide, andN-but-3-ynyl-C-(2-[trifluoromethyl]phenyl) methanesulfonamide.

The term mole % as used herein refers to the ratio of the moles of areactant to the moles of the compound of formula 2 or of formula 3,whichever is less.

As used herein, the term halogen refers to fluorine, chlorine, bromineand iodine. The term alkyl includes both straight and branched chainalkyl groups. The term alkoxy refers to alkyl, where alkyl is defined asdescribed above.

An embodiment of the present invention is shown below in Scheme 1.

In the reaction between the compounds of formulas 2 and 3, about half ofthe palladium catalyst can be combined with the compound of formula 3 ina first mixture, and the other half can be combined with the compound offormula 2, the CuI, and the base in a second mixture. The first mixturecan then be added slowly to the second.

The compound of formula 4 may be precipitated and recovered as a solidby filtration, leaving the bulk of the palladium catalyst in the motherliquor solution. If the palladium-catalyzed coupling reaction and indolecyclization reaction are concatenated, the palladium catalyst may beremoved during an extractive workup, for example, by washing the organicproduct layer with an aqueous solution of N-acetylcysteine, a procedureknown in the art. The solid precipitate may also be washed if additionalpalladium extraction is needed.

Following extraction of the palladium catalyst, the compound of formula4 is reacted with copper iodide in an aprotic solvent to induce indolecyclization. If the R₅ group is a carbamate (e.g., tert-butoxycarbonyl),it will be removed during this step. When this reaction is run at highertemperatures, the rate of cyclization generally is more rapid and fewerimpurities are found in the product. Suitable solvents include DMF, DMA,or the like. The reaction generally is run at a temperature at leastabout 100° C., preferably about 145-155° C. Although the reactants maybe mixed all at once, it is preferable to slowly add the compound offormula 4 to a hot solution of the copper iodide, especially when thereaction is carried out on large scale.

The compound of formula 6 may be obtained by any method known in theart, for example, by reacting the corresponding alkyl 4-iodobenzoatewith allyl alcohol in a stirred suspension of sodium bicarbonate,tetrabutyl-ammounium bromide and palladium (II) acetate in DMF. Thecompound of formula 6 may be purified, for example, by forming themetabisulfite salt 6a, as shown in Scheme 2 below.

For example, the compound of formula 6 may be dissolved in a suitableorganic solvent (e.g., toluene) and converted to the metabisulfite salt6a by addition of an aqueous metabisulfite solution. Although Scheme 2includes sodium metabisulfite (Na₂S₂O₅) as a reactant, othermetabisulfite salts (e.g., potassium metabisulfite, calciummetabisulfite) may be used. Separation of the organic layer removesorganic impurities. The metabisulfite salt 6a, which remains dissolvedin the aqueous layer, can then be converted back to the compound offormula 6 by reacting it with a base (e.g., potassium carbonate) in awater-ethyl acetate mixture and separating the ethyl acetate layer toisolate the compound. Using this method, the compound of formula 6 canbe isolated having a purity of greater than about 95%.

In one embodiment of the invention, the compounds of formulas 5 and 6are reacted with boron trifluoride etherate, trifluoroacetic acid andtriethylsilane in methylene chloride to produce the compound of formula7.

The compound of formula 7 can be converted to the compound of formula 1by treatment with base (e.g., a mixture of aqueous NaOH and THF inethanol) followed by lowering the pH (using, for example, an acid suchas aqueous acetic acid) to produce the compound of formula 1. Theproduct may be precipitated, for example, by reducing the solvent volumeand reducing the temperature.

Preferably, the compound of formula 7 is converted to the compound offormula 1 without previously isolating the compound of formula 7.Alternatively, the compound of formula 7 may be crystallized prior toconversion, for example, by evaporating the solvent to produce a syrup,and then stirring the syrup with ether and seed crystals. The compoundmay also be crystallized from an alcohol (e.g., methanol, ethanol,isopropanol, and the like) or any other suitable solvent.

The compound of formula 1 may be purified by recrystallization from avariety of solvent systems, for example, from toluene, toluene/heptanemixtures, ethyl acetate/heptane mixtures, and the like.Recrystallization from 100% ethanol has been shown to effectively purifythe compound without reducing yield.

Scheme 3 illustrates a route for making a compound of formula 3.

As illustrated in Scheme 3, the compound of formula 8 may be prepared,for example, by reacting a sulfonyl chloride 10 with aqueous or gaseousammonia to form a sulfonamide 11, which can then be protected as acarbamate, for example, by reacting with tert-butoxycarbonyl anhydride(BOC-anhydride). The reaction may be run at elevated temperature (e.g.,about 45° C.) in a solvent such as toluene and in the presence of4-dimethylaminopyridune (DMAP) and triethylamine (Et₃N).

The compound of formula 9 may be prepared by reacting 3-butyn-1-ol with4-chlorobenzenesulfonyl chloride in the presence of triethylamine intoluene. In this reaction, it is convenient to keep the reactiontemperature below about 20° C., as the triethylamine hydrochloride saltbyproduct precipitates and is readily separated by filtration. Theproduct can be precipitated from the solution, for example, by reducingthe solvent volume and adding propanol and cold water.

In one example according to the invention, the reaction between thecompounds of formulas 8 and 9 occurs in the presence of potassiumcarbonate granules or powder in DMF at elevated temperatures (e.g.,50-55° C.). The last step of Scheme 2, the removal of thetert-butoxycarbonyl (BOC) group, is optional, since either compound canbe used in the reaction in Scheme 1.

The reaction of compounds of formulas 8 and 9 is an example of ahomopropargylation reaction. Homopropargylation generally involves anSN₂ reaction using a homopropargyl precursor containing a leaving group,such as a halogen or tosylate. The methods known in the art may not besuitable for weaker nucleophiles, however, especially if the compoundincludes base sensitive functional groups. The triflate group (CF₃SO₃—)has been shown to be a good leaving group, but is relatively expensive.A milder method known in the art for introducing the homopropargyl groupinvolves a Mitsunobu type reaction with 3-butyn-1-ol andtriphenylphosphine. This reaction, however, suffers from pooratom-economy.

Using the methods of the present invention, SN₂-type homopropargylationreactions can be achieved under relatively mild conditions by using theleaving group p-chlorophenylsulfonyl. The homopropargylation reaction isshown in Scheme 4 below, in which Nu represents a nucleophile.

In addition to the advantages of relatively low cost and mildconditions, this process also has the advantage that the compound offormula 9 is a solid that can be prepared in high yield and is stable toextended storage at room temperature. The selectivity ofhomopropargylation using the compound of formula 9 is illustrated by thehigh yield (−90%) of the homopropargylations in the examples describedherein, using only a slight (<10%) molar excess of the compound offormula 9.

Examples of compounds that can be synthesized using the methods of thisinvention include those in which the groups R₁₋₄ have one of thecombinations of shown in the following table: Compound R¹ R² R³ R⁴ A CH₃H H H B CH₃ H H CH₃ C CF₃ H H H D H CF₃ H H E H H CF₃ H F CF₃ H H CF₃ GH H Cl H H Cl H H H I Cl H Cl H J H Cl Cl H K H Cl H H L OCF₃ H H H

The following examples are presented to illustrate certain embodimentsof the present invention, and should not be construed as limiting thescope of this invention.

EXAMPLE 1 Benzhydryl-(4-chloro-2-iodo-phenyl)-amine

A solution of benzhydrol (13.5 g, 73.3 mmol) and acetonitrile (56 mL)was added over 1 h to a warm (80° C.), stirred solution of2-chloro-4-iodoaniline (16 g, 63.1 mmol), benzenesulfonic acid (0.323 g,2.0 mmol) and acetonitrile (53 mL). The solution was maintained at 80°C. for an additional 2.5 h. The mixture was allowed to cool to roomtemperature. Water (31 mL) was added over 1 h to the stirred mixture.The mixture was stirred for 2 h at room temperature. The solid productwas collected by filtration. The solid product was combined withmethanol (67 mL) and warmed to reflux for 30 m. The mixture was allowedto cool to room temperature. The purified product was collected byfiltration, washed with methanol (2×10 mL) and vacuum dried to give 22.3g of benzhydryl-(4-chloro-2-iodo-phenyl)-amine with 99% purity (asdetermined by HPLC). Mp 107-110.

EXAMPLE 2 4-Chloro-benzenesulfonic acid but-3-ynyl ester

A solution of 3-butyn-1-ol (365 g, 5.21 mol), triethylamine (526 g, 5.21mol), and toluene (419 mL) was added to a cooled (0-5° C.) stirredsolution of 4-chlorobenzenesulfonyl chloride (1.0 kg, 4.74 mol) andtoluene (2.10 L). The reaction temperature was maintained below 20° C.during the addition. Precipitation of triethylamine hydrochloride saltoccurred during the reaction. The reaction mixture was stirred at roomtemperature for 2-4 h. The triethylamine hydrochloride byproduct wasseparated by filtration and washed with toluene (2×350 mL). The combinedfiltrates were concentrated to remove toluene under reduced pressureabove 45° C. to maintain the residue as a liquid. 2-Propanol (1.20 L)was added to the residue and the stirred solution was cooled to 20-25°C. Water (1.80 L) was added over 15 m. The slurry of product and solventwas cooled to 0-5° C. and stirred for 1 h. The white solid product wascollected by filtration, washed with 33% aqueous 2-propanol (v/v), andvacuum dried to give 4-chloro-benzenesulfonic acid but-3-ynyl ester with99% purity (as determined by HPLC.

EXAMPLE 3 (3,4-Dichloro-phenyl)-methanesulfonamide

A solution of (3,4-dichloro-phenyl)-methanesulfonyl chloride (500 g,1.93 mol) and acetone (470 mL) was added over 2 h to cooled (0-5° C.),stirred concentrated ammonium hydroxide (28%, 900 mL, 227 g NH₃, 13.3mol). The reaction mixture was maintained below 12° C. during theaddition. The reaction mixture was allowed to warm to room temperatureand was stirred for 1 h. Water (900 mL) was added to the reactionmixture and it was stirred for 1 h. The white solid was collected byfiltration, washed with cold water (2×500 mL), and vacuum dried to give375 g (81%) of (3,4-dichloro-phenyl)-methanesulfonamide with 99% purity(as determined by HPLC).

EXAMPLE 4 Carbamic acid,[(3,4-dichlorophenylmethyl)-sulfonyl]-1,1-dimethylethyl ester

A solution of di-tert-butyl-dicarbonate (390 g, 1.79 mol) and toluene(740 mL) was added over 1.5 h to a stirred, warm (45° C.) mixture of(3,4-dichloro-phenyl)-methanesulfonamide (370 g, 1.54 mol),4-dimethylaminopyridine (18.8 g, 0.154 mol), triethylamine (234 g, 2.32mol), and toluene (3.0 L). The reaction mixture was stirred at 45° C.for 2 h. The reaction mixture was cooled to 0-5° C. Tetrahydrofuran (185mL) was added to the reaction mixture A 10% aqueous solution ofphosphoric acid was added to the reaction mixture over 1 h, maintainingan internal temperature of <5 C. The organic phase was collected andwashed with 2.5% aqueous sodium bicarbonate (2.0 L). The combined waterphases were washed with tetrahydrofuran (200 mL). The combined organicphases were concentrated under reduced pressure to a volume of 2.5 L.The mixture was cooled in an ice bath, and heptane (3.7 L) was chargedover 15 m to complete product precipitation. The mixture was stirred at0-5° C. for 1-2 h. The product was collected by filtration, washed withheptane (2×750 mL), and vacuum dried at <35° C. to give 463 g (88%) ofcarbamic acid, [(3,4-dichlorophenylmethyl)sulfonyl]-, 1,1-dimethylethylester with 98% purity (as determined by HPLC).

EXAMPLE 5 N-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide

A mixture of carbamic acid, [(3,4-dichlorophenylmethyl)sulfonyl]-,1,1-dimethylethyl ester (443 g, 1.13 mol), 4-chloro-benzenesulfonic acidbut-3-ynyl ester (332.5 g, 1.36 mol), granular potassium carbonate (359g, 2.60 mol), and N,N-dimethylformamide (1.38 L) was combined stirred,and warmed to 55° C. The mixture was stirred and maintained at 50-55° C.for 21 h. Additional charges of potassium carbonate (about 40 g) wereadded at 4 h intervals. The mixture was cooled to 30° C. The potassiumcarbonate was removed by filtration. The potassium carbonate cake waswashed with DMF (2250 mL). Water (600 mL) was added to the stirredfiltrates over 30 m. The mixture was stirred at room temperature for 1-2h after complete water addition. The solid was collected by filtrationand washed with 50% v/v aqueous methanol (2×350 mL). The product wasvacuum dried at <50° C. to give 412 g (81%) ofN-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide with 99%purity (as determined by HPLC).

EXAMPLE 6N-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide

A warm (45° C.) solution ofN-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide (347 g,0.885 mol), dichlorobis(triphenylphosphine)palladium (II) (3.50 g, 4.99mmol), and DMF (700 mL) was added slowly over 8 h to a warm (55° C.),stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (350 g,0.833 mol), dichlorobis(triphenylphosphine)palladium (II) (3.5 g, 4.99mmol), copper (I) iodide (20.0 g, 0.105 mol), triethylamine, (259 g,2.56 mol), and DMF (250 mL). The reaction mixture was stirred andmaintained at 55° C. for 30 m after complete addition. The reactionmixture was distilled at reduced pressure using a heating bathtemperature of 40-45° C. to remove triethylamine. The reaction mixturewas filtered through a celite pad. The pad was washed with DMF (40 mL).2-Propanol (280 mL) was added to the filtrate. The mixture was warmed to55° C. Water (280 mL) was added slowly over 1 h to the stirred mixture.The stirred mixture was maintained at 55° C. for 30 m after completewater addition. The mixture was cooled to 10° C. The solid product wascollected by filtration and washed with cold 1/1 (v/v) IPA/water (2×300mL). The solid was vacuum dried at <50° C. to giveN-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide(534.5 g, 94%) with 98% purity (as determined by HPLC).

EXAMPLE 7N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide

A solution ofN-t-butoxycarbonyl-N-{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide(400 g, 0.585 mol) and N,N-dimethylacetamide (800 mL) was added slowlyover 1 h to a hot (150° C.), stirred mixture of copper (I) iodide (12.2g, 0.064 mol) and N,N-dimethylacetamide (740 mL). The reaction mixturewas stirred and maintained at 150° C. for an additional 2 h. Thereaction mixture was cooled to 40° C. The mixture was filtered through acelite pad and the pad was washed with IPA (2×100 mL). An additionalcharge of IPA (1400 mL) was added to the filtrate. The mixture wasstirred and warmed to 60° C. Water (2.2 L) was added to the mixture over30 m, maintaining an internal temperature of 55-60° C. The mixture washeld at 60° C. for 30 m, then it was cooled to 5° C. The solid productwas collected by filtration and the cake was washed with cold IPA/water(3/2 v/v, 2×200 mL). The solid was vacuum dried at <50° C. to giveN-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide (338 g,99%) with 98% purity (as determined by HPLC).

EXAMPLE 84-{3-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

A solution of boron trifluoride etherate (50.7 g, 0.357 mol) andmethylene chloride (83 mL) was added over 10 min to a stirred, cooled(−20° C.) mixture ofN-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide(275 g, 0.471 mol), triethylsilane (1.42 mol), 4-(3-oxo-propyl)-benzoicacid ethyl ester (213.6 g, 1.04 mol), and methylene chloride (2.6 L). Anexotherm was observed and the reaction temperature increased to −13° C.The reaction mixture was cooled to and maintained at −20° C.Trifluoroacetic acid (53.7 g, 0.471 mol) was added to the reactionmixture 30 min after complete addition of boron trifluoride. Thereaction mixture was stirred at −20° C. for 2 h. The reaction mixturewas added to a stirred solution of sodium bicarbonate (127 g, 1.51 mol)and water (1.37 L). The mixture was filtered through a celite pad andthe pad was washed with methylene chloride (50 mL). The layers wereseparated. The aqueous layer was washed with methylene chloride (200mL). The combined organic layers were concentrated to 1.1 L at ambientpressure. Ethanol (1.38 L) was added to the mixture. The mixture wasconcentrated to 1.1 L at ambient pressure. The stirred mixture wascooled to 50° C. and tetrahydrofuran (275 mL) and 50% aqueous sodiumhydroxide (188 g, 2.35 mol) was added. The mixture was warmed to refluxfor 30 min. The mixture was cooled to 50° C. and toluene (1.38 L), water(225 mL), and acetic acid (141 g, 2.35 mol) was added. The mixture wasstirred for 30 min. The mixture was filtered through a celite pad. Thelayers were separated and the aqueous layer was washed with a solutionof tetrahydrofuran and toluene (1/1 v/v, 100 mL). The organic layer waswashed consecutively with 3% aqueous sodium bicarbonate (100 ml),saturated sodium chloride (100 mL), and water (2×125 mL). The organiclayer was concentrated to 1.1 L at ambient pressure. Toluene (550 mL)was added and the mixture was concentrated to 1.1 L at ambient pressure.The mixture was allowed to cool to room temperature and stirredovernight. Heptane (110 mL) was added to the stirred mixture afterprecipitation of solid product was observed. The solid product wascollected by filtration and washed with cold toluene (2×275 mL). Theproduct was vacuum dried at 66° C. to give4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid (227 g, 65%) with a purity of 99% (as determined by HPLC). Theproduct can be recrystallized from ethanol in 91% recovery. MP 190° C.

EXAMPLE 9 4-(3-Oxo-propyl)-benzoic acid ethyl ester

Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087mol) are added to a stirred suspension of Sodium bicarbonate (152 g,1.812 mol), tetrabutyl-ammounium bromide (117 g, 0.362 mol) andPalladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reactionmixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C. -50°C. Toluene (1 L) is added to the reaction mixture with vigorousagitation and the mixture is stirred for 15 min at room temperature. Theresulting mixture is filtered through a celite pad. The pad is washedwith toluene (2×200 mL). The filtrate and wash are combined, washed withwater (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained.¹H NMR (DMSO-d₆): δ1.38 (t, 3H), 2.81 (t, 2H), 3.03 (t, 2H), 4.39 (q,2H), 7.27 (d, 2H), 7.98 (d, 2H), 9.81 (s, 1H).

EXAMPLE 10 Purification of 4-(3-Oxo-propyl)-benzoic acid ethyl ester

Crude 4-(3-Oxo-propyl)-benzoic acid ethyl ester (52% purity asdetermined by HPLC) was dissolved in toluene (80 mL) and combined withwater (100 mL). The mixture was stirred. A solution of sodiummetabisulfite (55.4 g) and water (130 mL) was added over 45 min to thestirred solution. The reaction mixture was warmed to 32° C. for 1 h. Thelayers were separated and the aqueous layer was washed with toluene(2×25 mL). The layers were separated. Water (600 mL) and ethyl acetate(150 mL) were added to the aqueous layer. The mixture was stirred andcooled to 2° C. A solution of potassium carbonate (165 g) and water (160mL) was added over 1 h to the stirred reaction mixture, maintaining aninternal temperature of 0-2° C. The reaction mixture was warmed to20-23° C. in 1 h and then stirred for 2 h. The layers were separated andthe aqueous layer was washed with ethyl acetate (2×20 mL). The combinedorganic layers were washed with water (2×50 mL). The ethyl acetate wasremoved under reduced pressure at <24° C. to give purified4-(3-Oxo-propyl)-benzoic acid ethyl ester (20.6 g, 41% recovery). Thepurity was 96% (as determined by HPLC). Mp 109° C.

EXAMPLE 11 (2,6-Dimethylphenyl)-methanesulfonamide

A solution of (2,6-dimethylphenyl)-methanesulfonyl chloride (452 g, 2.07mol) and acetone (2.0 L) was added over 90 m to cooled (0-5° C.),stirred, concentrated ammonium hydroxide (28%, 900 mL, 227 g NH₃, 13.3mol). The reaction mixture was maintained <10° C. during the addition.The reaction mixture was allowed to warm to room temperature and wasstirred for 1 h. Water (2.0 L) was added to the reaction mixture and itwas stirred for 1 h at 0-5° C. The white solid was collected byfiltration, washed with cold water (2×1 L), and vacuum dried to give 349g (85%) of (2,6-dimethylphenyl)-methanesulfonamide with 99% purity (asdetermined by HPLC).

EXAMPLE 12 Carbamic acid,[(2,6-dimethylphenyl)methyl-sulfonyl]-1,1-dimethylethyl ester

A solution of di-tert-butyl-dicarbonate (490 g, 2.25 mol) and toluene(100 mL) was added over 3 h to a stirred, warm (40° C.) mixture of(2,6-dimethylphenyl)-methanesulfonamide (325 g, 1.63 mol),4-dimethylaminopyridine (19.9 g, 0.163 mol), triethylamine (248 g, 2.46mol), and toluene (2.60 L). The reaction mixture was stirred at 40° C.for 2 h. The reaction mixture was cooled to 0-5° C. Tetrahydrofuran (650mL) was added to the reaction mixture. A 10% aqueous solution ofphosphoric acid (2.6 L) was added to the reaction mixture over 1 h,maintaining an internal temperature of <5 C. The organic phase wascollected and washed with water (650 mL). The organic phase wascollected and washed with 5% aqueous sodium bicarbonate (650 mL). Thecombined organic phases were concentrated under reduced pressure to avolume of 1.7 L. The mixture was cooled in an ice bath, and heptane(3.25 L) was charged over 1 hour to complete product precipitation. Themixture was stirred at 0-5° C. for 1-2 h. The product was collected byfiltration, washed with heptane (2×650 mL), and vacuum dried at <35° C.to give 427 g (87%) of carbamic acid,[(2,6-dimethylphenyl)methylsulfonyl]-, 1,1-dimethylethyl ester with 98%purity (as determined by HPLC).

EXAMPLE 13 N-BOC-N-but-3-ynyl-(2,6-Dimethylphenyl)-methanesulfonamide

A mixture of carbamic acid, [(2,6-dimethylphenyl)methylsulfonyl]-,1,1-dimethylethyl ester (415 g, 1.38 mol), 4-chloro-benzenesulfonic acidbut-3-ynyl ester (349 g, 1.43 mol), granular potassium carbonate (382 g,2.77 mol), and N,N-dimethylformamide (1.29 L) was combined stirred, andwarmed to 50-55° C. The mixture was stirred and maintained at 50-55° C.for 21 h. Additional charges of potassium carbonate (about 40 9) wereadded at 4 h intervals. The mixture was cooled to 30° C. The potassiumcarbonate was removed by filtration. The potassium carbonate cake waswashed with DMF (2×230 mL). Water (560 mL) was added to the stirredfiltrates over 30 m. The mixture was stirred at room temperature for 1-2h after complete water addition. The solid was collected by filtrationand washed with 50% v/v aqueous methanol (2×330 mL). The product wasvacuum dried at <50° C. to give 436 g (90%) ofN-BOC-N-but-3-ynyl-(2,6-dimethylphenyl)-methanesulfonamide with 99%purity (as determined by HPLC).

EXAMPLE 14N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide

A warm (40-45° C.) solution ofN-Boc-N-but-3-ynyl-(2,6-dimethylphenyl)-methanesulfonamide (44.4 g,0.106 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713mmol), and DMF (125 mL) was added slowly over 7 h to a warm (55° C.),stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (50 g,0.119 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713mmol), copper (I) iodide (3.0 g, 15.7 mmol), triethylamine, (42.2 g,0.418 mol), and DMF (75 mL). Toluene (250 mL) and water (250 mL) wereadded to the reaction mixture. The aqueous phase was separated andwashed with toluene (2×100 mL). The combined organic phases werefiltered through a celite pad. The filtrate was washed with an 8.3%aqueous solution of N-acetylcysteine (2×150 mL), then again with water(150 mL). The organic phase was washed with 5% aqueous sodiumbicarbonate (150 mL), then again with water (150 mL). The organic phasewas concentrated to a heavy oil under reduced pressure. The oil wasdissolved in N,N-dimethylacetamide (DMA, 175 mL). This DMA solution wasadded over 1 hour to a stirred mixture of copper iodide (2.26 g, 11.8mmol) and DMA at 150° C. The reaction mixture was stirred at 150° C. foran additional 2.25 hours. The reaction mixture was cooled to roomtemperature and filtered through a celite pad with a DMA wash (2×25 mL).2-Propanol (400 mL) was added to the warmed (45-40° C.), stirredfiltrate. Then water (600 mL) was added to the stirred, warm (45-50° C.)mixture over 1 hour. The mixture was cooled to room temperature andstirred for a minimum of 12 hours. The solid was collected by filtrationand washed with 2-propanol (2×50 mL). The solid was vacuum dried at 50°C. to giveN-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide(60.6 g, 94%) with 98% purity (as determined by HPLC).

EXAMPLE 154-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

A solution of boron trifluoride etherate (55 g, 0.387 mol) and methylenechloride (75 mL) was added over 10 min to a stirred, cooled (−20° C.)mixture ofN-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide(300 g, 0.552 mol), triethylsilane (192 g,1.66 mol),4-(3-oxo-propyl)-benzoic acid ethyl ester (250 g, 1.21 mol), andmethylene chloride (2.8 L). An exotherm was observed and the reactiontemperature increased to −9° C. The reaction mixture was cooled to andmaintained at −20° C. Trifluoroacetic acid (63 g, 0.553 mol) was addedto the reaction mixture 30 min after complete addition of borontrifluoride. The reaction mixture was stirred at −20° C. for 2 h. Thereaction mixture was added to a stirred solution of sodium bicarbonate(138 g, 1.64 mol) and water (1.50 L). The mixture was filtered through acelite pad and the pad was washed with methylene chloride (150 mL). Thelayers were separated. The aqueous layer was washed with methylenechloride (300 mL). The combined organic layers were concentrated to 1.2L at ambient pressure. Ethanol (1.50 L) was added to the mixture. Themixture was concentrated to 1.2 L at ambient pressure. The stirredmixture was cooled to 50° C. and tetrahydrofuran (450 mL) and 50%aqueous sodium hydroxide (221 g, 2.76 mol) was added. The mixture waswarmed to reflux for 30 min. The mixture was cooled to 50° C. andtoluene (1.50 L), water (300 mL), and acetic acid (166 g, 2.76 mol) wasadded. The mixture was stirred for 30 min. The mixture was filteredthrough a celite pad. The layers were separated and the aqueous layerwas washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100mL). The organic layer was washed consecutively with 3% aqueous sodiumbicarbonate (100 ml), saturated sodium chloride (100 mL), and water(2×125 mL). The organic layer was concentrated to 1.2 L at ambientpressure. Toluene (600 mL) was added and the mixture was concentrated to1.2 L at ambient pressure. The mixture was allowed to cool to roomtemperature and stirred overnight. Heptane (100 mL) was added to thestirred mixture after precipitation of solid product was observed. Thesolid product was collected by filtration and washed with cold toluene(3×300 mL). The product was vacuum dried at 66° C. to give4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid (317 g, 81%) with a purity of 96% (as determined by HPLC). Theproduct can be recrystallized from ethanol/water in 91% recovery. MP193° C.

EXAMPLE 16 Ethyl4-{3-[5-chloro-2-(2-{[(2,6-dimethylbenzyl)-sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate

To a stirred mixture ofN-{2-[5-chloro-1-(diphenylmethyl)-1H-indol-2-yl]ethyl}-1-(2,6-dimethylphenyl)methanesulfonimide(35.00 g, 64.44 mmol) and ethyl 4-(3-oxopropyl)benzoate (29.24 g, 141.77mmol) in dichloromethane (250 mL) cooled to −5° C. was addedtriethylsilane (31 mL, d=0.728, 194.08 mmol) with a rinse ofdichloromethane (100 mL). Cooling was continued to −20° C. A solution ofboron trifluoride etherate (5.50 mL. d=1.12, 43.40 mmol) indichloromethane (40 mL) was added dropwise over 5 min. The temperaturerose to −15° C. When the temperature had dropped to −20° C. once more,the remnants of the boron trifluoride etherate were rinsed into thereaction vessel with dichloromethane (30 mL). The temperature wasmaintained between −15° C. and −20° C. for 40 min. Trifluoroacetic acid(5.0 mL, d=1.48, 64.90 mmol) was added and the stirred mixture was keptat −15° C. and −20° C. for 3 hours with monitoring with HPLC [85.89%yield (at 220 nm and excluding excess ethyl 4-(3-oxopropyl)benzoate)].The mixture was poured into a stirred aqueous solution of sodiumbicarbonate (20 g in 220 mL water) and stirred for 5 hours, allowing themixture to warm to room temperature. The mixture was refrigeratedovernight. The mixture was filtered and the layers were allowed toseparate in a separatory funnel (100 mL rinse to complete transfer). Thelight blue aqueous phase was separated and the organic phase was washedwith water (3×100 mL) until the washings were pH 7 (pH paper). Thevolume was made up 650 mL with dichloromethane. A 200 mL portion at roomtemperature was removed and distilled to a volume of 160 mL. The stirredsolution was then distilled while adding dropwise 2B ethanol (260 mL) atsuch a rate that the level of liquid in the distillation flask remainedat the 160 mL mark. The final boiling point of the solution was 80-80.5°C. The solution was allowed to cool. It was seeded at 68° C., allowed tocool to 50° C. and placed in a water bath at 50° C. The slurry ofcrystals was allowed to cool slowly to 26° C., and then to 5-10° C. withan ice/water bath. Further cooling to −10° C. was achieved using a dryice/acetone bath. The stirred slurry was kept at −20° C. for 15 min andthen filtered. The filter cake was washed with cold (−20° C.) 2B ethanol(3×20 mL). The mother liquor and washings deposited more product onstanding. The wet cake weighed 17.68 g. After drying overnight in avacuum oven at 54° C. the crushed product (weighing 9.52 g) was driedonce more overnight to provide 9.46 g (65%). HPLC purity (area %) of thematerial was 97.84%. NMR data was consistent with the product.

Variations of the present invention not illustrated herein will occur tothose skilled in the art. The present invention is not limited to theembodiments illustrated and described herein, but encompasses all thesubject matter within the scope of the appended claims.

1. A method for making a compound of formula 1:

said method comprising the steps of: a) reacting compounds of formulas 2and 3:

to produce a compound of formula 4:

wherein: R¹, R², R³, and R⁴ each is independently selected from thegroup consisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl; and R⁵ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl, said reaction occurring in the presence of abase, a palladium catalyst, and a copper catalyst; and b) converting thecompound of formula 4 to the compound of formula
 1. 2. The method ofclaim 1, wherein R¹, R², R³, and R⁴ each is independently selected fromthe group consisting of H, halogen, —CF₃, and —C₁₋₆ alkyl.
 3. The methodof claim 2, wherein R¹ is H, R² is Cl, R³is Cl, and R⁴ is H.
 4. Themethod of claim 2, wherein R¹ is —CF₃, R² is H, R³is H, and R⁴is H. 5.The method of claim 1, wherein at least about 2 equivalents of the baseare present.
 6. The method of claim 5, wherein about 2-4 equivalents ofthe base are present.
 7. The method of claim 1, wherein about 0.5 mole %to about 1.5 mole % of the palladium catalyst is present.
 8. The methodof claim 1, wherein at least about 5 mole % of the copper catalyst ispresent.
 9. The method of claim 8, wherein about 5 mole % to about 15mole % of the copper catalyst is present
 10. The method of claim 1,wherein the base is selected from the group consisting of atrialkylamine, an alkali earth metal carbonate, an alkali earth metalbicarbonate, an alkaline earth metal carbonate, and an alkaline earthmetal bicarbonate.
 11. The method of claim 10, wherein the base isdiisopropylethylamine, triethylamine, or a combination thereof.
 12. Themethod of claim 1, wherein step b) comprises the step of reacting thecompound of formula 4 with copper iodide to produce a compound offormula 5:


13. The method of claim 12, wherein step b) further comprises the stepof reacting the compound of formula 5 with a compound of formula 6:

to produce a compound of formula 7:


14. The method of claim 13, wherein the compound of formula 6 ispurified by: a) treating the compound of formula 6 with aqueousmetabisulfite solution to form a metabisulfite salt of the formula 6a:

wherein M is Na or K, and b) treating the metabisulfite salt of formula6a with a base to form the compound of formula
 6. 15. The method ofclaim 13, wherein step b) further comprises the step of reacting thecompound of formula 7 with a base to remove the ester C₁₋₆ alkyl group.16. The method of claim 15, wherein the compound of formula 7 is notisolated prior to reacting with the base.
 17. The method of claim 15,wherein the compound of formula 7 is isolated by crystallization priorto reacting with the base.
 18. The method of claim 15, furthercomprising the step of recrystallizing the compound of formula 1 from asolvent comprising an alcohol.
 19. The method of claim 18, wherein thealcohol is ethanol.
 20. The method of claim 1, wherein the compound offormula 2 is prepared by reacting 2-iodo-4-chloroaniline with benzhydrolin the presence of an acid.
 21. The method of claim 1 wherein thecompound of formula 3 is prepared by reacting a compound of formula 8with a compound of formula 9:

in the presence of a base, wherein R⁵is —C(O)O—C₁l alkyl.
 22. A compoundof formula 3:

wherein: R¹, R², R³, and R⁴ each is independently selected from thegroup consisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl; and R⁵ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl.
 23. The compound of claim 22, wherein R¹, R², R³,and R⁴ each is independently selected from the group consisting of H,halogen, —CF₃, and —C₁₋₆ alkyl.
 24. The compound of claim 23, wherein R¹is H, R² is Cl, R³is Cl, and R⁴ is H.
 25. The compound of claim 23,wherein R¹ is —CF₃, R²is H, R³is H, and R⁴is H.
 26. The compound ofclaim 22, selected from the group consisting of:N-but-3-ynyl-C-(2,6-dimethylphenyl)methanesulfonamide,N-but-3-ynyl-C-(3,4-dichlorophenyl)methanesulfonamide, andN-but-3-ynyl-C-(2-[trifluoromethyl]phenyl)methanesulfonamide.
 27. Amethod for making a compound of formula 4:

comprising the step of reacting compounds of formulas 2 and 3:

wherein: R₁, R₂, R₃, and R⁴ each are independently selected from thegroup consisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, C₁ alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl; and R₅ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl, said reaction occurring in the presence of abase, a palladium catalyst, and a copper catalyst.
 28. The method ofclaim 27 wherein R₁, R₂, R₃, and R₄ each is independently selected fromthe group consisting of H and halogen.
 29. The method of claim 28,wherein R¹ is H, R² is Cl, R³ is Cl, and R⁴ is H.
 30. The method ofclaim 28, wherein R¹ is —CF₃, R²is H, R³ is H, and R⁴ is H.
 31. Themethod of claim 27, wherein at least about 2 equivalents of base arepresent.
 32. The method of claim 27, wherein about 0.5 mole % to about1.5 mole % of the palladium catalyst is present.
 33. The method of claim27, wherein about 5 mole % to about 15 mole % of the copper catalyst ispresent
 34. The method of claim 27, wherein the base is selected fromthe group consisting of a trialkylamine, an alkali earth metalcarbonate, an alkali earth metal bicarbonate, an alkaline earth metalcarbonate, and an alkaline earth metal bicarbonate.
 35. The method ofclaim 34, wherein the base is diisopropylethylamine, triethylamine, or acombination thereof.
 36. A compound of formula 4:

wherein: R₁, R₂, R₃, and R⁴ each are independently selected from thegroup consisting of H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —NO₂, —C₁₋₆alkyl, Con alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, and—NHC(O)—C₁₋₆ alkyl; and R₅ is selected from the group consisting of Hand —C(O)O—C₁₋₆ alkyl.
 37. The compound of claim 36, wherein R¹, R², R³,and R⁴ each is independently selected from the group consisting of H,halogen, —CF₃, and -C₁₋₆ alkyl.
 38. The compound of claim 37, wherein R¹is H, R² is Cl, R³ is Cl, and R⁴is H.
 39. The compound of claim 37,wherein R¹ is —CF₃, R² is H, R³ is H, and R⁴ is H.